DISCUSSION
To our knowledge, this is the
first meta-analysis of trials exclusively carried out in
children and adolescent populations that explored the efficacy of adding
ICS to SC compared with SC alone for acute asthma when consulting in the
ED or during hospitalization. Our study demonstrates that in children
hospitalized with an acute asthma episode adding budesonide
significantly reduces the LOS by more than one day. Among the trials
done in the ED, adding budesonide significantly improved the acute
asthma severity score, especially when using high doses of budesonide
(≥2 mg).
Objective measurements such as SpO2 and respiratory and
heart rates were significantly different between children treated with
the addition of budesonide versus controls. The SpO2improved, while respiratory and heart rates decreased in the budesonide
group only among trials with hospitalized children; however, not pooled
data analysis was able to performed. It is important to mention that
heart rate could be influenced by the SABA drugs included in the
protocol. In terms of lung function, only two studies (one in the ED and
one in hospitalized children) reported this outcome, and in both
children on ICS+SC significantly improved the PEFR in comparison with
SC. The same result was before described in adults using PEFR, but not
with FEV18. Similarly, the present review shows that
adding budesonide to SC does not result in more AEs or SAEs, as was
described in the last Cochrane review8.
The most recent GINA guidelines4 stated that a high
dose of ICS within the first hours after presentation to ED reduces the
need for hospitalization in patients who did not receive SC, but the
addition of ICS to SC is inconclusive, and the type of ICS, doses, and
duration remain unclear; moreover, the cost is an issue that remains to
be resolved. Likewise, the latest Cochrane review8 of
five studies (n=433 patients), but only two
studies20,23 in children, showed that ICS plus SC
significantly reduces hospital admission compared with SC, but with high
heterogenicity (OR=0.54 [0.36 to 0.81], I2=52%),
and stated the necessity for further research “to clarify the most
appropriate drug dosage and delivery device, and to define which
patients are most likely to benefit from ICS therapy”. Our systematic
review of nine studies done exclusively in a population of children with
acute asthma (n=1473) showed that adding budesonide via nebulizer did
not reduce hospital admission, but significantly reduces the LOS, and
improves the asthma severity score in the ED, especially when using high
doses of budesonide. In terms of cost, in a recent cost-effectiveness
analysis done in a middle-high income country, we demonstrated that ICS
in addition to SCs compared with standard therapy with SCs for treating
pediatric asthma model showed that compared to SCs, therapy with ICS+SCs
was associated with lower total costs (US$ 88.8 vs.US$97.7 average
cost per patient) and a lower probability of hospital admission (0.9060
vs. 0.9000)29.
The biological explanation of the superiority of adding ICS to SC vs. SC
is the addition of the non-genomic effect, which only ICS exhibit (i.e.
activation of endothelial NO synthase and NO synthesis, increasing the
noradrenergic neurotransmission in the airway vasculature and therefore
reducing the airway blood flow10, a desirable effect
in asthmatic patients, where a significant increased blood flow in the
airway mucosa ocurrs11), to the genomic effect of SC.
Another advantage of adding ICS is their very rapid onset of action (in
minutes) in contrast to the slow onset of action of SCs (3–4 h after
administration). An additional mechanism is that ICS administration
simultaneously with SABA could acutely potentiate its bronchodilation
effect30.
In all the RCTs included in this systematic review, the ICS used was
budesonide. A study in vivo31 showed that budesonide
oleate is formed rapidly in human airways after inhalation and is
detectable in lung tissue for almost 2 days after a single inhalation.
Esterification takes place intracellularly within the lungs, and the
sustained action of budesonide is explained by this fatty acid
conjugation. This sustained retention of esterified budesonide in the
lungs supports the prolonged duration of action of budesonide and its
suitability for once-daily administration31.
Budesonide, compared with other ICS, had the highest vasoconstrictive
effect in airway blood flow32,33, and since airway
blood flow is increased in asthmatics, the vasoconstrictive effect of
ICS is beneficial. Also, when budesonide was nebulized up to 26% of the
drug is systemically bioavailable in children34.
This study has several limitations. First, no studies using ICS delivery
by MDI were found, and therefore the results of budesonide via nebulizer
cannot be extrapolated to ICS delivery via MDI or to other types of ICS.
Also, it was not possible to evaluate the relative efficacy of the
different nebulizer devices used in these trials. Second, only two
studies measured lung function. Third, differences in type of SC was not
analysis in detail. Fourth, the minimal clinically important difference
for each asthma score using in the trials was not reported. Five, since
better results were obtained using 2mg doses of budesonide, more trials
with higher doses need to be performed. The strength of this study is
that it includes nine RCTs exclusively carried out in a population of
children, most of them with high-quality methodology, from seven
different countries around the world involving more than 1400 patients
with asthma.
In conclusion, adding budesonide to SC, compared with SC alone, for
acute asthma in hospitalized children significantly reduces the LOS by
more than one day, and significantly improves the acute asthma severity
score for patients in the ED (especially using ≥2 mg).
List of Abbreviations: AEs= adverse effects, API= asthma
predictive index, ED= emergency department, ICS= inhaled
corticosteroids, LOS= length of stay, MDI= metered dose inhaler, NO=
nitric oxide, PEFR= peak expiratory flow rate, RCTs= randomized clinical
trials, RR= risk ratios, SAEs= severe adverse effects, SABA= beta-2
agonists, SpO2= oxygen saturation, SC= systemic
corticosteroids, SMD= standardized mean differences.